Brain tumors are a prevalent pediatric malignancy, and of these medulloblastoma is the most common. However, in most cases a detailed understanding of the molecular basis of medulloblastoma is lacking. Therefore, genetically defined animal models of medulloblastoma will be important for insight into these tumors, and will yield critical information that will be applicable to the human situation. With the exception of mice heterozygous for the Patched-1 gene, there is a paucity of available animal models of medulloblastoma. Clearly, additional mouse models will be valuable for establishing common molecular themes that may be important for medulloblastoma formation and progression. We found that all mice with inactive DNA Ligase IV (Lig4) and p53 develop medulloblastoma by nine weeks of age. Consequently, we propose experiments to expand on this finding. We will test our hypothesis that a selective predisposition of the developing cerebellum to endogenous DNA damage is a factor in the etiology of medulloblastoma. We will characterize the Lig4-/-p53-/- medulloblastoma at the molecular, cell biological and cytogenetic level, to determine the similarities to other mouse or human medulloblastoma. Additionally, to gain insight into tumor biology, we will use comparative gene expression profiling of tumor and normal tissue. To do this, we will employ DNA microarray analysis to comprehensively determine characteristic gene expression profiles within and between different medulloblastomas, to identify cohorts of genes that may be central to the formation and maintenance of the transformed state. Finally, we will evaluate the role of DNA damage in the genesis of medulloblastoma by generating a Lig4 conditional allele to determine if genetic instability alone arising from DNA Ligase IV deficiency is sufficient for the formation of medulloblastoma. We will also assess if brain regions other than the cerebellum are equally susceptible (both with and without p53) to neoplastic transformation. These experiments will increase our understanding of the molecular basis of medulloblastoma, and should be important for providing a rational basis to design novel therapeutic approaches for the treatment of these tumors.